CA2862885C - Pharmaceutical compositions containing dimethyl fumarate - Google Patents
Pharmaceutical compositions containing dimethyl fumarate Download PDFInfo
- Publication number
- CA2862885C CA2862885C CA2862885A CA2862885A CA2862885C CA 2862885 C CA2862885 C CA 2862885C CA 2862885 A CA2862885 A CA 2862885A CA 2862885 A CA2862885 A CA 2862885A CA 2862885 C CA2862885 C CA 2862885C
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- CA
- Canada
- Prior art keywords
- dosage form
- oral dosage
- solid oral
- dmf
- dimethyl fumarate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 title claims abstract description 202
- 229960004419 dimethyl fumarate Drugs 0.000 title claims abstract description 200
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 11
- 239000000203 mixture Substances 0.000 claims abstract description 169
- 238000000034 method Methods 0.000 claims abstract description 27
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 22
- 238000000576 coating method Methods 0.000 claims description 64
- -1 hydroxyl propyl Chemical group 0.000 claims description 54
- 239000011248 coating agent Substances 0.000 claims description 50
- 239000006186 oral dosage form Substances 0.000 claims description 44
- 239000007787 solid Substances 0.000 claims description 43
- 239000002775 capsule Substances 0.000 claims description 37
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 34
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 33
- 238000011010 flushing procedure Methods 0.000 claims description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 31
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 30
- 229920001577 copolymer Polymers 0.000 claims description 26
- 239000000945 filler Substances 0.000 claims description 25
- 239000000314 lubricant Substances 0.000 claims description 24
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 22
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 22
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 16
- 239000007884 disintegrant Substances 0.000 claims description 16
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 13
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 13
- 239000000377 silicon dioxide Substances 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 11
- 239000001913 cellulose Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 238000005056 compaction Methods 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 229920002678 cellulose Polymers 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- 235000010980 cellulose Nutrition 0.000 claims description 7
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 6
- 101000945318 Homo sapiens Calponin-1 Proteins 0.000 claims description 6
- 101000652736 Homo sapiens Transgelin Proteins 0.000 claims description 6
- 102100031013 Transgelin Human genes 0.000 claims description 6
- 239000008119 colloidal silica Substances 0.000 claims description 6
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 claims description 6
- OSNIIMCBVLBNGS-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-2-(dimethylamino)propan-1-one Chemical compound CN(C)C(C)C(=O)C1=CC=C2OCOC2=C1 OSNIIMCBVLBNGS-UHFFFAOYSA-N 0.000 claims description 5
- 239000001856 Ethyl cellulose Substances 0.000 claims description 5
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 5
- 229920001249 ethyl cellulose Polymers 0.000 claims description 5
- 235000013305 food Nutrition 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 2
- NZEXUPLJXSDMCK-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;methyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound COC(=O)C=C.CC(=C)C(O)=O.COC(=O)C(C)=C NZEXUPLJXSDMCK-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical group OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 202
- NKHAVTQWNUWKEO-UHFFFAOYSA-N fumaric acid monomethyl ester Natural products COC(=O)C=CC(O)=O NKHAVTQWNUWKEO-UHFFFAOYSA-N 0.000 abstract description 59
- NKHAVTQWNUWKEO-NSCUHMNNSA-N monomethyl fumarate Chemical compound COC(=O)\C=C\C(O)=O NKHAVTQWNUWKEO-NSCUHMNNSA-N 0.000 abstract description 59
- 229940005650 monomethyl fumarate Drugs 0.000 abstract description 58
- 150000003839 salts Chemical class 0.000 abstract description 26
- 238000011321 prophylaxis Methods 0.000 abstract description 9
- 208000015122 neurodegenerative disease Diseases 0.000 abstract description 5
- 230000004770 neurodegeneration Effects 0.000 abstract description 3
- 125000000217 alkyl group Chemical group 0.000 description 85
- 239000001257 hydrogen Substances 0.000 description 61
- 229910052739 hydrogen Inorganic materials 0.000 description 61
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 54
- 125000003118 aryl group Chemical group 0.000 description 36
- 239000002552 dosage form Substances 0.000 description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 33
- 235000002639 sodium chloride Nutrition 0.000 description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 26
- 238000011282 treatment Methods 0.000 description 24
- 208000024891 symptom Diseases 0.000 description 22
- 238000012360 testing method Methods 0.000 description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 20
- 239000002702 enteric coating Substances 0.000 description 20
- 238000009505 enteric coating Methods 0.000 description 20
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 17
- 125000001424 substituent group Chemical group 0.000 description 17
- 239000003826 tablet Substances 0.000 description 17
- 239000000843 powder Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 15
- 239000004615 ingredient Substances 0.000 description 15
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 15
- 229940016286 microcrystalline cellulose Drugs 0.000 description 15
- 239000008108 microcrystalline cellulose Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- 239000000454 talc Substances 0.000 description 15
- 235000012222 talc Nutrition 0.000 description 15
- 229910052623 talc Inorganic materials 0.000 description 15
- 230000002496 gastric effect Effects 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Natural products OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 13
- 125000001072 heteroaryl group Chemical group 0.000 description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 13
- 229940068196 placebo Drugs 0.000 description 12
- 239000000902 placebo Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 125000006686 (C1-C24) alkyl group Chemical group 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 229940033134 talc Drugs 0.000 description 11
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 11
- 150000002431 hydrogen Chemical class 0.000 description 10
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000011230 binding agent Substances 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- 229920000642 polymer Polymers 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 239000001530 fumaric acid Substances 0.000 description 7
- 239000004014 plasticizer Substances 0.000 description 7
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 description 6
- 125000000172 C5-C10 aryl group Chemical group 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 208000007118 chronic progressive multiple sclerosis Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- QRKPLLLQZJCOLR-BWEANOATSA-N 6-[(1r,2r,3s)-2-[(z)-4-carboxybut-2-enyl]-3-hydroxy-5-oxocyclopentyl]-4-oxohexanoic acid Chemical compound O[C@H]1CC(=O)[C@H](CCC(=O)CCC(O)=O)[C@H]1C\C=C/CC(O)=O QRKPLLLQZJCOLR-BWEANOATSA-N 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 230000006835 compression Effects 0.000 description 5
- 238000007906 compression Methods 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 5
- 230000010412 perfusion Effects 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 229940032147 starch Drugs 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 210000002700 urine Anatomy 0.000 description 5
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 4
- 239000001506 calcium phosphate Substances 0.000 description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- HNEGQIOMVPPMNR-NSCUHMNNSA-N mesaconic acid Chemical compound OC(=O)C(/C)=C/C(O)=O HNEGQIOMVPPMNR-NSCUHMNNSA-N 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 229910000077 silane Inorganic materials 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 4
- 239000001069 triethyl citrate Substances 0.000 description 4
- 235000013769 triethyl citrate Nutrition 0.000 description 4
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 208000007400 Relapsing-Remitting Multiple Sclerosis Diseases 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 3
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 235000011010 calcium phosphates Nutrition 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
- 229960005168 croscarmellose Drugs 0.000 description 3
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 229960002900 methylcellulose Drugs 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 229940068968 polysorbate 80 Drugs 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229940083037 simethicone Drugs 0.000 description 3
- 235000010413 sodium alginate Nutrition 0.000 description 3
- 239000000661 sodium alginate Substances 0.000 description 3
- 229940005550 sodium alginate Drugs 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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| US61/723,048 | 2012-11-06 | ||
| PCT/US2013/024946 WO2013119677A1 (en) | 2012-02-07 | 2013-02-06 | Pharmaceutical compositions containing dimethyl fumarate |
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| CA2526586C (en) | 2003-09-09 | 2010-03-16 | Fumapharm Ag | The use of fumaric acid derivatives for treating cardiac insufficiency, and asthma |
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| LT2139467T (lt) * | 2007-02-08 | 2016-10-10 | Biogen Ma Inc. | Neuroapsauga, sergant demielinizuojančia liga |
| EP2334378B1 (en) | 2008-08-19 | 2014-04-09 | XenoPort, Inc. | Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions thereof, and methods of use |
| MX355421B (es) | 2011-06-08 | 2018-04-18 | Biogen Ma Inc | Proceso para preparar fumarato de dimetilo cristalino y de alta pureza. |
| BR112014019462B1 (pt) * | 2012-02-07 | 2022-03-22 | Biogen Ma Inc. | Composições farmacêuticas contendo fumarato de dimetila |
| US9597292B2 (en) | 2012-08-22 | 2017-03-21 | Xenoport, Inc. | Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof |
| CA2882713A1 (en) * | 2012-08-22 | 2014-02-27 | Xenoport, Inc. | Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects |
| EP3566701A1 (en) | 2012-12-21 | 2019-11-13 | Biogen MA Inc. | Deuterium substituted fumarate derivatives |
| CA2906580C (en) | 2013-03-14 | 2019-10-29 | Alkermes Pharma Ireland Limited | Prodrugs of fumarates and their use in treating various diseases |
| US8669281B1 (en) | 2013-03-14 | 2014-03-11 | Alkermes Pharma Ireland Limited | Prodrugs of fumarates and their use in treating various diseases |
| WO2014143146A1 (en) * | 2013-03-15 | 2014-09-18 | Xenoport, Inc. | Methods of administering monomethyl fumarate |
| WO2014160633A1 (en) | 2013-03-24 | 2014-10-02 | Xenoport, Inc. | Pharmaceutical compositions of dimethyl fumarate |
| US9302977B2 (en) | 2013-06-07 | 2016-04-05 | Xenoport, Inc. | Method of making monomethyl fumarate |
| WO2014205392A1 (en) | 2013-06-21 | 2014-12-24 | Xenoport, Inc. | Cocrystals of dimethyl fumarate |
| EP3041467A1 (en) | 2013-09-06 | 2016-07-13 | XenoPort, Inc. | Crystalline forms of (n,n-diethylcarbamoyl)methyl methyl (2e)but-2-ene-1,4-dioate, methods of synthesis and use |
| KR102353201B1 (ko) | 2013-12-12 | 2022-01-18 | 알미랄, 에스.에이. | 디메틸 푸마레이트를 포함하는 약학적 조성물 |
| US10172794B2 (en) | 2013-12-13 | 2019-01-08 | Biogen Ma Inc. | Controlled release dosage form for once daily administration of dimethyl fumarate |
| US9604922B2 (en) | 2014-02-24 | 2017-03-28 | Alkermes Pharma Ireland Limited | Sulfonamide and sulfinamide prodrugs of fumarates and their use in treating various diseases |
| ES2713157T3 (es) * | 2014-02-28 | 2019-05-20 | Banner Life Sciences Llc | Cápsulas blandas entéricas de liberación controlada de ésteres de fumarato |
| US9326947B1 (en) | 2014-02-28 | 2016-05-03 | Banner Life Sciences Llc | Controlled release fumarate esters |
| US10098863B2 (en) | 2014-02-28 | 2018-10-16 | Banner Life Sciences Llc | Fumarate esters |
| US9636318B2 (en) | 2015-08-31 | 2017-05-02 | Banner Life Sciences Llc | Fumarate ester dosage forms |
| MA51730A (fr) | 2014-03-14 | 2020-12-16 | Biogen Ma Inc | Fumarate de diméthyle et régimes de vaccination |
| US9999672B2 (en) | 2014-03-24 | 2018-06-19 | Xenoport, Inc. | Pharmaceutical compositions of fumaric acid esters |
| CA2962916C (en) * | 2014-10-08 | 2021-06-15 | Banner Life Sciences Llc | Controlled release enteric soft capsules of fumarate esters |
| CA2965449C (en) * | 2014-10-27 | 2020-11-10 | Cellix Bio Private Limited | Three component salts of fumaric acid monomethyl ester with piperazine or ethylene diamine for the treatment of multiple sclerosis |
| MA40985A (fr) | 2014-11-17 | 2017-09-26 | Biogen Ma Inc | Méthodes de traitement de la sclérose en plaques |
| MA40990A (fr) * | 2014-11-19 | 2017-09-26 | Biogen Ma Inc | Formulations de matrice pharmaceutique comprenant du fumarate de diméthyle |
| MA40982A (fr) * | 2014-11-19 | 2017-09-26 | Biogen Ma Inc | Formulation de bille pharmaceutique comprenant du fumarate de diméthyle |
| CN104490849A (zh) * | 2014-11-24 | 2015-04-08 | 广东东阳光药业有限公司 | 一种高密度的富马酸二甲酯肠溶颗粒及其制备方法 |
| MA41139A (fr) | 2014-12-11 | 2017-10-17 | Actelion Pharmaceuticals Ltd | Combinaison pharmaceutique comportant un agoniste sélectif du récepteur sip1 |
| MX379273B (es) | 2014-12-11 | 2025-03-11 | Actelion Pharmaceuticals Ltd | Regimen de dosificación para un agonista selectivo de receptor s1p1. |
| HK1253050A1 (zh) * | 2015-02-02 | 2019-06-06 | 英仕柏集团有限责任公司 | 稳定的富马酸二烷基酯组合物 |
| EP3253377B1 (en) * | 2015-02-08 | 2021-05-12 | Alkermes Pharma Ireland Limited | Monomethylfumarate prodrug compositions |
| WO2016147108A1 (en) * | 2015-03-17 | 2016-09-22 | Hetero Research Foundation | Pharmaceutical compositions of dimethyl fumarate |
| MA41785A (fr) | 2015-03-20 | 2018-01-23 | Biogen Ma Inc | Procédés et compositions pour l'administration intraveineuse de fumarates pour le traitement de maladies neurologiques |
| US10085961B2 (en) | 2015-06-01 | 2018-10-02 | Sun Pharmaceutical Industries Limited | Pharmaceutical compositions of dimethyl fumarate |
| AU2016279997B2 (en) | 2015-06-17 | 2021-10-21 | Biogen Ma Inc. | Dimethyl fumarate particles and pharmaceutical compositions thereof |
| WO2017056107A1 (en) * | 2015-09-28 | 2017-04-06 | Natco Pharma Ltd | Pharmaceutical compositions of dimethyl fumarate |
| CA3003237A1 (en) * | 2015-10-28 | 2017-05-04 | Sun Pharmaceutical Industries Limited | Pharmaceutical compositions of dimethyl fumarate |
| ES2953440T3 (es) * | 2015-12-31 | 2023-11-13 | Zakl Farmaceutyczne Polpharma Sa | Proceso para la preparación de un granulado con recubrimiento entérico que comprende fumarato de dimetilo |
| PL3407873T3 (pl) * | 2016-01-28 | 2025-01-13 | Zakłady Farmaceutyczne POLPHARMA S.A. | Sposób otrzymywania granulatu zawierającego fumaran dimetylu |
| EP3413879A1 (en) * | 2016-02-11 | 2018-12-19 | Biogen MA Inc. | Pharmaceutical bead formulations comprising dimethyl fumarate |
| WO2017145036A1 (en) * | 2016-02-25 | 2017-08-31 | Aurobindo Pharma Ltd | Pharmaceutical compositions comprising dimethyl fumarate |
| TR201616998A1 (en) | 2016-11-23 | 2018-06-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | DELAYED RELEASE DOSING FORMS WITH DIMETHYL FUMARATE |
| WO2018170319A1 (en) * | 2017-03-17 | 2018-09-20 | Vitalis Llc | Compositions and methods for treating multiple sclerosis |
| CN110636838A (zh) | 2017-06-23 | 2019-12-31 | 阿尔米雷尔有限公司 | 包含反丁烯二酸二甲酯的药物组合物 |
| US20210251910A1 (en) * | 2018-09-10 | 2021-08-19 | Vitalis Llc | Fumaric acid compositions with increased bioavailability and reduced side effects |
| US11446055B1 (en) | 2018-10-18 | 2022-09-20 | Lumoptik, Inc. | Light assisted needle placement system and method |
| TR201818293A2 (tr) | 2018-11-30 | 2020-06-22 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Di̇meti̇l fumarat i̇çeren geci̇kmeli̇ salim sağlayan kapsül |
| WO2021142062A1 (en) * | 2020-01-10 | 2021-07-15 | Banner Life Sciences Llc | Fumarate ester dosage forms with enhanced gastrointestinal tolerability |
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| JP2023525079A (ja) | 2020-05-06 | 2023-06-14 | アンシス・エスア | フマレート関連疾患の併用療法 |
| MX2023014395A (es) * | 2021-06-04 | 2023-12-15 | Zim Laboratories Ltd | Composiciones de liberacion retardada de dimetilfumarato. |
| WO2023119037A1 (en) | 2021-12-23 | 2023-06-29 | Gencaps Sàrl | Drug delivery system comprising monomethyl fumarate |
| CN115590831A (zh) * | 2022-10-26 | 2023-01-13 | 力品药业（厦门）股份有限公司（Cn） | 一种富马酸二甲酯缓释微片及其制备方法 |
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| WO2010079221A1 (en) | 2009-01-09 | 2010-07-15 | Forward Pharma A/S | Pharmaceutical composition comprising one or more fumaric acid esters |
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| BR112014019462B1 (pt) * | 2012-02-07 | 2022-03-22 | Biogen Ma Inc. | Composições farmacêuticas contendo fumarato de dimetila |
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